Inflammation in the CNS causes a wide range of clinical disorders including Multiple Sclerosis (MS). During an MS attack, inflammation in the central nervous system (CNS) can produce partial or complete paralysis. There is, as yet, no cure for MS. In the current study, we will test the effect of resveratrol (RES; 3,5,4'-trihydroxystilbene) on experimental autoimmune encephalomyelitis (EAE), an animal model of MS primarily triggered by activation of CD4+ MBP reactive Th1 and Th17 cells. Our laboratory was the first one to demonstrate that treatment with RES can ameliorate EAE. Moreover, we made an exciting and unique discovery that RES triggers induction of a recently characterized immunoregulatory cell called myeloid derived suppressor cell (MDSC). Based on our preliminary studies, we will test the hypothesis that RES suppresses neuroinflammation during EAE through epigenetic regulation and microRNA (miR) induction leading to the generation and activation of MDSCs which suppress myelin-specific T cells. Furthermore, we will test if the MDSC induction results from the activation of aryl hydrocarbon receptor (AhR) and/or estrogen receptor (ER) by RES. Understanding the precise mechanisms underlying the effects of RES on immune response against myelin may offer effective strategies to prevent induction and progression of the disease in MS as well as neuroinflammation associated with a number of other disorders. Aim 1: We will test the central hypothesis that RES activates AhR/ER to induce granulocyte colony stimulating factor (G-CSF) and arginase 1 (Arg1), which trigger differentiation of MDSCs from hematopoietic progenitor cells and their activation respectively. We will investigate the role of AhR and ER in the induction of MDSCs. We will investigate the transcriptional regulation of G-CSF and arginase 1 (Arg1) involving dioxin responsive elements (DRE) or estrogen-responsive elements (ERE) found on the promoters of these genes. Aim 2: We will test the central hypothesis that RES triggers MDSCs through epigenetic regulation of genes involved in MDSC differentiation and functions. The role of DNA methylation as well as histone modification will be determined in RES-induced MDSC in EAE mice by assessing genome-wide methylation using MeDip- Seq and ChiP-Seq, and by determining locus-specific methylation status. The DNA methylation and histone marks in the specific gene promoters of CD11b and Gr-1 as well as arginase 1 and iNOS will be validated. Aim 3: We will test the central hypothesis that RES induces miRNA that target specific genes involved in MDSC differentiation and functions. We will identify the role of miR223 that is induced by RES in hematopoietic stem cell differentiation into MDSC. We will also test whether the downregulation of miR185 and miR340 leads to increased iNOS and arginase production respectively. Together, our studies should provide novel information on how RES suppresses neuroinflammation through the induction of MDSCs via epigenetic regulation.